The invention relates to specific saccharide compositions and methods for treating Alzheimer""s disease and other amyloidoses; more particularly, it relates to compositions and methods for therapeutic intervention in Alzheimer""s disease and other amyloidoses involving the use of substituted anionic groups in mono and poly saccharides or pharmaceutically acceptable salts thereof.
Alzheimer""s disease is characterized by the accumulation of a 39-43 amino acid peptide termed the beta-amyloid protein or Axcex2, in a fibrillar form, existing as extracellular amyloid plaques and as amyloid within the walls of cerebral blood vessels. Fibrillar Axcex2 amyloid deposition in Alzheimer""s disease is believed to be detrimental to the patient and eventually leads to toxicity and neuronal cell death, characteristic hallmarks of Alzheimer""s disease. Accumulating evidence implicates amyloid as a major causative factor of Alzheimer""s disease pathogenesis.
A variety of other human diseases also demonstrate amyloid deposition and usually involve systemic organs (i.e. organs or tissues lying outside the central nervous system), with the amyloid accumulation leading to organ dysfunction or failure. In Alzheimer""s disease and xe2x80x9csystemicxe2x80x9d amyloid diseases, there is currently no cure or effective treatment, and the patient usually dies within 3 to 10 years from disease onset.
Much work in Alzheimer""s disease has been accomplished, but little is conventually known about compounds or agents for therapeutic regimes to arrest amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer""s disease and other amyloidoses.
New compounds or agents for therapeutic regimes to arrest or reverse amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer""s disease and other amyloidoses are therefore desperately needed.
A primary object of the present invention is to establish new methods and compositions which are useful for the treatment of the amyloid diseases. The amyloid diseases include, but are not limited to, the amyloid associated with Alzheimer""s disease, Down""s syndrome and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (wherein the specific amyloid is referred to as beta-amyloid protein or Axcex2), the amyloid associated with chronic inflammation, various forms of malignancy and Familial Mediterranean Fever (wherein the specific amyloid is referred to as AA amyloid or inflammation-associated amyloidosis), the amyloid associated with multiple myeloma and other B-cell dyscrasias (wherein the specific amyloid is referred to as AL amyloid), the amyloid associated with type II diabetes (wherein the specific amyloid is referred to as amylin or islet amyloid), the amyloid associated with the prion diseases including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru and animal scrapie (wherein the specific amyloid is referred to as PrP amyloid), the amyloid associated with long-term hemodialysis and carpal tunnel syndrome (wherein the specific amyloid is referred to as beta2-microglobulin amyloid), the amyloid associated with senile cardiac amyloid and Familial Amyloidotic Polyneuropathy (wherein the specific amyloid is referred to as transthyretin or prealbumin), and the amyloid associated with endocrine tumors such as medullary carcinoma of the thyroid (wherein the specific amyloid is referred to as variants of procalcitonin).
The methods of the invention involve administering to a subject the therapeutic compound glucose pentasulfate, and pharmaceutically acceptable salts thereof, or derivatives thereof, which inhibit amyloid formation, deposition, accumulation and/or persistence, and/or which cause dissolution/disruption of pre-existing amyloid. Accordingly, the compositions and methods of the invention are useful for inhibiting amyloidosis in disorders in which amyloid deposition occurs. The methods of the invention can be used therapeutically to treat amyloidosis or can be used prophylactically in a subject susceptible to amyloidosis. The methods of the invention result, at least in part, in directly inhibiting or causing a reduction in the beta-pleated sheet secondary structure of specific amyloid proteins, such as, but not limited to, the beta-amyloid protein (Axcex2) of Alzheimer""s disease and the islet amyloid polypeptide (i.e. amylin) of type II diabetes.
xe2x80x9cDerivativesxe2x80x9d, xe2x80x9crelated derivativesxe2x80x9d, xe2x80x9cderivatives thereofxe2x80x9d or xe2x80x9cclosely related compoundsxe2x80x9d of glucose pentasulfate for the purposes of this application shall include but are not limited to, glucose monosulfate, glucose disulfate, glucose trisulfate, glucose tetrasulfate, and glucose pentasulfate existing as a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, pentasaccharide, hexasaccharide, heptasaccharide, hexasaccharide, nonasaccharide, decasaccharide or other polysaccharides of increasing length. In addition, xe2x80x9cderivativesxe2x80x9d of glucose pentasulfate, include but are not limited to, glucose pentasulfate, pharmaceutically acceptable salts thereof, and derivatives (referred to above) which have been substituted at sulfate-containing positions with other anionic group(s). Preferred substitutions include, but are not limited to, the replacement of sulfates with phosphates, phosphonates, carboxylates, sulphonates, and/or any ring compounds (i.e. alicyclic or heterocyclic groups) containing anionic groups. In addition, multiple anionic groups can be of the same structural group (i.e. all carboxylates) or, alternatively, a combination of different anionic groups can be used (i.e. carboxylates and phosphates).
An xe2x80x9canionic groupxe2x80x9d of a therapeutic compound of the invention is a negatively charged moiety. For purposes of the invention, the anionic group is negatively charged at physiological pH.
As used herein, the term xe2x80x9cmonosaccharidexe2x80x9d are simple sugars usually of the formula C6H12O6 that can be combined to form oligosaccharides or polysaccharides. Monosaccharide include enantiomers and both the D and L stereoisomers of monosaccharide. Carbohydrates, which include substituted and unsubstituted mono, oligo, and polysaccharides, can have multiple anionic groups attached to each monosaccharide moiety.
Another object of the present invention is to use the saccharide glucose pentasulfate and related derivatives for the treatment of amyloid formation, deposition, accumulation and/or persistence in Alzheimer""s disease, type II diabetes and other amyloidoses. However, the glucose pentasulfate may exist as a monosaccharide, or as saccharides of increasing length (i.e. polysaccharides) such as, but not limited to, disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, hexasaccharides, heptasaccharides, octasaccharides, nonasaccharides, or decasaccharides.
Another object of the present invention is to use glucose pentasulfate and related derivatives for the treatment of amyloid formation, deposition, accumulation and/or persistence in Alzheimer""s disease, type II diabetes and other amyloidoses.
Another object of the present invention is to use commercially available, or to make commercially available, pills, tablets, caplets, soft and hard gelatin capsules, lozenges, sachets, cachets, vegicaps, liquid drops, elixers, suspensions, emulsions, solutions, syrups, tea bags, aerosols (as a solid or in a liquid medium), suppositories, sterile injectable solutions, and/or sterile packaged powders, which contain glucose pentasulfate or related derivatives to treat patients with Alzheimer""s disease, type II diabetes and other amyloidoses.
Yet another object of the present invention is to use glucose pentasulfate or related derivatives as potent agents which inhibit amyloid formation, amyloid deposition, amyloid accumulation, amyloid persistence, amyloid-proteoglycan/glycosaminoglycan (PG/GAG) interactions, and/or cause a dissolution of pre-formed or pre-deposited amyloid fibrils in Alzheimer""s disease, type II diabetes and other amyloidoses.
Yet another object of the present invention is to provide the use of glucose pentasulfate or related derivatives (regardless of commercial source) for inhibition of amyloid formation, deposition, accumulation, and/or persistence, regardless of its clinical setting.
Yet another object of the present invention is to provide compositions and methods involving administering to a subject a therapeutic dose of glucose pentasulfate or related derivatives which inhibit amyloid deposition. Accordingly, the compositions and methods of the invention are useful for inhibiting amyloidosis in disorders in which amyloid deposition occurs. The compounds of the invention can be used therapeutically to treat amyloidosis or can be used prophylactically in a subject susceptible to amyloidosis. The methods of the invention result, at least in part, in directly inhibiting amyloid fibril formation and/or causing dissolution of preformed amyloid fibrils. It is believed that glucose pentasulfate""s mechanism of action works by directly inhibiting B-pleated sheet secondary structure folding of particular amyloid proteins (ie. with unique amino acid sequences), such as, but not limited to, the beta-amyloid protein (Axcex2) of Alzheimer""s disease and the islet amyloidpolypeptide (i.e. amylin) of type II diabetes.
Yet another object of the present invention is to provide pharmaceutical compositions for treating amyloidosis. The pharmaceutical compositions include a therapeutic compound of the invention in an amount effective to inhibit amyloid deposition and a pharmaceutically acceptable vehicle.
Yet another object of the present invention is the use of any and all synthetic compounds to glucose pentasulfate or related derivatives for use as potent agents which inhibit amyloid formation, amyloid deposition, amyloid accumulation, amyloid persistence, amyloid-PG/GAG interactions, and/or cause a dissolution of pre-formed or pre-deposited amyloid fibrils in Alzheimer""s disease, type II diabetes and other amyloidoses.
Yet another object of the present invention is to provide the use of glucose pentasulfate and/or derivatives thereof [(regardless of commercial source and regardless of final form for consumption by humans, i.e. pills, tablets, caplets, soft and hard gelatin capsules, lozenges, sacchets, vegicaps, liquid drops, elixers, suspensions, emulsions, solutions, syrups, tea bags, aerosols (as a solid or in a liquid medium), suppositories, sterile injectable solutions, and/or sterile packaged powders] for inhibition of amyloid formation, deposition, accumulation, and/or persistence, regardless of its clinical setting.
Yet another object of the present invention is the use of any and all natural compounds (i.e. plant, animal or mineral) to glucose pentasulfate or related derivatives for use as potent agents which inhibit amyloid formation, amyloid deposition, amyloid accumulation, amyloid persistence, amyloid-PG/GAG-interactions, and/or cause a dissolution of pre-formed or pre-deposited amyloid fibrils in Alzheimer""s disease, type II diabetes and other amyloidoses.
It is yet another object of the invention to meet any or all of the needs summarized above.
These and such other objects of the invention as will become evident from the disclosure below are met by the invention disclosed herein.
One aspect of the invention is a pharmaceutical agent for treating an amyloid disease in a patient, wherein the pharmaceutical agent comprises a therapeutically effective amount of a saccharide containing at least one substituted anionic group, or a pharmaceutically acceptable salt of the saccharide containing one or more substituted anionic groups. The agent may also advantageously include a pharmaceutically acceptable carrier, diluent or excipient. The saccharide is preferably a saccharide selected from the group consisting of all monosaccharides, disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, hexasaccharides, heptasaccharides, octasaccharides, nonasaccharides, and decassacharides. A preferred embodiment of the saccharide is a monosaccharide, and more preferably the monosaccharide is glucose. The therapeutically effective amount preferably has an amyloid inhibitory activity or efficacy of 40% or greater.
The saccharide preferably contains at least one substituted anionic group selected from the group consisting of all sulfates, sulphonates, phosphates, phosphonates, carboxylates. A preferred substituted anionic group is sulfate.
The agent is preferably selected from the group consisting of glucose monosulfate, glucose disulfate, glucose trisulfate, glucose tetrasulfate, glucose pentasulfate, and more preferably is glucose pentasulfate, or a pharmaceutically acceptable salt thereof, such as a potassium salt.
The therapeutically effective amount of glucose pentasulfate may be obtained from any commercially available source, such as pills, tablets, caplets, soft and hard gelatin capsules, lozenges, sachets, cachets, vegicaps, liquid drops, elixers, suspensions, emulsions, solutions, syrups, tea bags, aerosols (as a solid or in a liquid medium), suppositories, sterile injectable solutions, or sterile packaged powders, or made available in such forms.
Another aspect of the invention is method of treating an amyloid disease in a patient, comprising the step of administering to the patient a therapeutically effective amount of glucose pentasulfate, a pharmaceutically acceptable salt thereof, or a related derivative thereof. The therapeutically effective amount of glucose pentasulfate is preferably administered orally, by aerosol spray, or in a parenterally injectable or infusible form.
The present invention pertains in particular to the identification and surprising discovery that the saccharide glucose pentasulfate acts as an impressive inhibitor of Alzheimer""s disease amyloid formation, and as a potent agent which causes the dissolution of pre-formed amyloid fibrils containing the Alzheimer""s disease beta-amyloid protein (Axcex2), and to a lesser extent the amyloid fibrils of type II diabetes (i.e. islet amyloid polypeptide or amylin).
It has been found that commercially available glucose pentasulfate caused a marked inhibition of Axcex2 amyloid fibril formation as determined using a Thioflavin T fluorometry assay. In direct comparison, other compounds containing an identical number of sulfate groups (i.e. five) such as mannose pentasulfate, and other sugars and/or sulfated-containing compounds such as sucrose octasulfate, sucrose hexasulfate, sucrose heptasulfate, methyl alpha-D-mannopyranoside 2,3,4,6-tetrasulfate, and methyl alpha-D-glucopyranoside 2,3,4,6-tetrasulfate, were all ineffective inhibitors of Axcex2 amyloid fibril formation, indicating the specificity observed with glucose pentasulfate. The inhibition by glucose pentasulfate on Axcex2 amyloid fibril formation occurred in a dose-dependent manner. In addition, glucose pentasulfate was found to be a potent dissolving agent of pre-formed Alzheimer""s Axcex2 amyloid fibrils, as determined using a Thioflavin T fluorometry assay. This latter effect occurred in a dose-dependent manner and within a 4 day incubation period. Glucose pentasulfate also caused a dissolution of fibrils containing islet amyloid polypeptide (i.e. amylin) by 1 week of incubation. Lastly, glucose pentasulfate was also effective in the inhibition of Axcex2-PG/GAG interactions as determined using a solid phase binding immunoassay. The latter inhibition by glucose pentasulfate on Axcex2-PG/GAG interactions also occurred in a dose-dependent manner.
It is believed that one possible mechanism of action for glucose pentasulfate is by directly inhibiting xcex2-pleated sheet secondary structure folding of particular amyloid proteins (ie. with unique amino acid sequences), such as, but not limited to, the beta-amyloid protein (Axcex2) of Alzheimer""s disease. Glucose pentasulfate which was effective in all of the studies described above was derived from commercial available glucose pentasulfate in a water soluble form, making it easily adaptable for oral use in humans. A particular aspect of the present invention is the use of glucose pentasulfate (or related derivatives) (in a pill, tablet or liquid form) from commercial sources for the treatment of amyloidosis in Alzheimer""s disease and other amyloidoses. Use of glucose pentasulfate is expected to be beneficial to human patients at all stages of Alzheimer""s disease, due to glucose pentasulfate""s inherent ability to inhibit Axcex2 amyloid fibril formation (early to mid-stage Alzheimer""s disease), cause dissolution of preformed amyloid fibrils (mid to late stages of Alzheimer""s disease) and inhibit amyloid-PG/GAG interactions (all stages of Alzheimer""s disease).
These and other features and advantages of the present invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying figures.
In other aspects of the invention, a pharmaceutical agent is disclosed for treating an amyloid disease in a patient, wherein the pharmaceutical agent comprises a therapeutically effective amount of glucose pentasulfate or derivatives thereof. The pharmaceutical agent preferably has a therapeutically effective amount of glucose pentasulfate or derivatives thereof in a dosage in the range of from about 5 to 10,000 mg/kg of body weight of the patient, per day, and more preferably in the range of from about 5 to 500 mg/kg of body weight of the patient, per day.
The amyloid disease for treatment with the pharmaceutical agent is selected from the group consisting of the amyloid associated with Alzheimer""s disease, Down""s syndrome and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (wherein the specific amyloid is referred to as beta-amyloid protein or Axcex2), the amyloid associated with chronic inflammation, various forms of malignancy and Familial Mediterranean Fever (wherein the specific amyloid is referred to as AA amyloid or inflammation-associated amyloidosis), the amyloid associated with multiple myeloma and other B-cell dyscrasias (wherein the specific amyloid is referred to as AL amyloid), the amyloid associated with type II diabetes (wherein the specific amyloid is referred to as amylin or islet amyloid), the amyloid associated with the prion diseases including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru and animal scrapie (wherein the specific amyloid is referred to as PrP amyloid), the amyloid associated with long-term hemodialysis and carpal tunnel syndrome (wherein the specific amyloid is referred to as beta2-microglobulin amyloid), the amyloid associated with senile cardiac amyloid and Familial Amyloidotic Polyneuropathy (wherein the specific amyloid is referred to as transthyretin or prealbumin), and the amyloid associated with endocrine tumors such as medullary carcinoma of the thyroid (wherein the specific amyloid is referred to as variants of procalcitonin).
Active compounds are administered at a therapeutically effective dosage sufficient to inhibit amyloid formation, deposition, accumulation or persistence in a subject. A therapeutically effective dosage preferably inhibits amyloid formation, deposition, accumulation or persistence by at least 20%, more preferably by at least 40%, even more preferably by at least 60%, and still more preferably by at least 80% relative to untreated subjects.